A high percentage of infants born today have been exposed in utero to cocaine. Little information is available regarding the ontogeny of most neurotransmitter systems in the normal human brain and we know virtually nothing about the direct molecular effects of prenatal cocaine/polydrug exposure in the human fetal brain. Clinical investigations have reported behavioral disturbances, e.g., in attention, arousal, stress responsitivity, affect, and motor function in children exposed prenatally to cocaine, and animal studies have linked some of these disturbances to impaired limbic and basal ganglia function. The neurobiological basis of these behavioral distrurbances is unknown. However, results from several experimental studies suggest that some of these abnormalities might be mediated by alterations in dopamine (DA) function. In addition to DAergic changes, cocaine administration in adults has consistently been found to alter the prodynorphin opioid neuropeptide gene expression. Based on these experimental studies, we hypothesize that DA and opioid neuropeptide systems might be vulnerable to cocaine exposure during the development of the human brain. Gene expression is a fundamental component of neural development and can provide information regarding cell differentiation and cell response to changes in the microenvironment. By using in situ hybridization histochemistry in conjunction with morphometry we will study; (1) the ontogeny of opioid neuropeptide and DA-related genes during normal human development, (2) whether early-to-mid gestational cocaine/polydrug exposure in the human fetus causes discrete regional and cellular alterations of DA and opioid neuropeptide gene expression in the striatum and cortex, and (3) whether there is a specific limbic neural vulnerability for the effects of in utero cocaine/polydrug exposure in humans in regards to e.g. the patch versus matrix striatal compartments. Before any final judgement can be made as to the developmental outcome of individuals exposed prenatally to cocaine/polydrug, it is necessary to know the direct neuronal consequences of intrauterine cocaine exposure. If future therapeutic interventions are deemed necessary for these individuals, then a better understanding of which cellular populations are vulnerable to in utero cocaine exposure will aid in the development of targeted pharmacological treatments.